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Derivatives of CGRP

a technology of derivatives and cgrp, which is applied in the field of derivatives of cgrp, can solve the problems of preventing the complete understanding of the actions

Active Publication Date: 2012-09-27
EPOQE PHARMA APS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent is about a type of compound called acylated CGRP. The technical effect of this invention is that it provides a way to modify the structure of CGRP compounds, which could have potential therapeutic benefits.

Problems solved by technology

Due to vasodilatory effects of administered CGRP, in vivo pharmacological studies of native CGRP are contaminated with effects secondary to vasodilation and to compensatory vasoconstrictive actions.
Thus, the vasodilatory action is the dose limiting action of CGRP which prevents the complete understanding of the actions relevant to metabolic syndrome.
Thus, the pharmacological usefulness of CGRP requires the generation of CGRP analogues with prolonged action and some effects may even only be obtained with prolonged analogues.

Method used

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  • Derivatives of CGRP
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Examples

Experimental program
Comparison scheme
Effect test

example 1

N-alpha-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetyl][Ser1]alpha-human CGRP peptide

[0205]

[0206]Preparation: SPPS method A, starting with H-PAL HMPB-ChemMatrix resin (loading 0.43 mmol / g, 0.582 g, 0.25 mmol). The following pseudo prolines employed are available from Novabiochem; Fmoc-Leu-Ser(ψMe,Mepro)-OH and Fmoc-Val-Thr(ψMe,Mepro)-OH. Building block 8-(9-fluorenylmethyloxycarbonylamino)-3,6-dioxaoctanoic acid are commercially available from Iris Biotech and octadecanedioic acid mono tert-butyl ester was prepared as described in WO 2005 / 012347.

[0207]HPLC 08_B2—1: 11.90 min.

[0208]HPLC 08_B4—1: 7.88 min.

[0209]HPLC 04_A4—1: 10.16 min.

[0210]LCMS: m / z=1459.2 (M+3H)3+, 1094.5 (M+4H)4+, 875.6 (M+5H)5+

example 2

N-alpha-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetyl][Ser1]beta-human CGRP peptide

[0211]

[0212]Preparation: SPPS method B starting with ChemMatrix Rink Amide resin (0.25 mmol). The following amino acids were double coupled; glycine (position 20) and glycine (position 14). Building block 8-(9-fluorenylmethyloxycarbonylamino)-3,6-dioxaoctanoic acid are commercially available from Iris Biotech and octadecanedioic acid mono tert-butyl ester was prepared as described in WO 2005 / 012347.

[0213]HPLC 08_B4—1: 8.31 min.

[0214]HPLC 04_A3—1: 13.52 min.

[0215]LCMS: m / z=1461.1 (M+3H)3+, 1096.3 (M+4H)4+

example 3

N-alpha-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetyl]alpha-human CGRP peptide

[0216]

[0217]Preparation: SPPS method A, starting with H-PAL HMPB-ChemMatrix resin (loading 0.43 mmol / g, 0.582 g, 0.25 mmol). The following pseudo prolines employed are available from Novabiochem; Fmoc-Leu-Ser(ψMe,Mepro)-OH and Fmoc-Val-Thr(ψMe,Mepro)-OH. Building block 8-(9-fluorenylmethyloxycarbonylamino)-3,6-dioxaoctanoic acid are commercially available from Iris Biotech and octadecanedioic acid mono tert-butyl ester was prepared as described in WO 2005 / 012347.

[0218]HPLC 08_B4—1: 8.21 min.

[0219]HPLC 08_B2—1: 12.39 min.

[0220]HPLC 05_B5—1: 5.15 min.

[0221]HPLC 04_A3—1: 13.27 min.

[0222]LCMS: m / z=1453.69 (M+3H)3+, 1090.50 (M+4H)4+, 872.42 (M+5)5+

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Abstract

Acylated CGRP compounds with a linker have prolonged action and are valuable as medicaments.

Description

FIELD OF THIS INVENTION[0001]The present invention relates to novel derivatives of CGRP and aspects related thereto.BACKGROUND OF THIS INVENTION[0002]The metabolic syndrome is manifested by obesity, insulin resistance, dyslipidaemia and hypertension. Today, the four manifestations are treated by selective treatment paradigmes.[0003]Calcitonin gene-related peptide (hereinafter designated CGRP) is a peptide which, in several species, exists in two forms, designated CGRP-alpha and CGRP-beta (or CGRP-I and CGRP-II, respectively). CGRP peptides are highly concerved within species. For example, the amino acid sequences of human and rat CGRP peptides are mentioned in table 1 in Peptides 20 (1999), 275-84. CGRP is released from, e.g., sensory, motor and enteric nerves.[0004]From the literature it is evident that CGRP triggers various pharmacological effects, e.g.: 1) vasodilation, 2) muscle and liver AMP kinase (AMPK) activation and lipolysis and / or fat oxidation, 3) reduction in food intak...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K14/585A61P5/48A61K38/23A61P9/12A61P9/00A61P3/10A61P3/04
CPCA61K47/48176A61K47/48192C07K14/57527A61K47/48246A61K47/48215A61K47/60A61K47/58A61K47/59A61K47/64A61P3/04A61P5/48A61P9/00A61P9/12A61P3/10
Inventor NIELSEN, ANETTE SAMSKRUSE, THOMASKODRA, JANOS TIBORLAU, JESPER F.KOFOED, JACOBRAUN, KIRSTENNILSSON, CECILIA
Owner EPOQE PHARMA APS
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